Novel antibacterial amide compounds and process means for producing the same

ABSTRACT

Novel organic amide compounds which are N-[6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]penicillin and cephalosporin type compounds having broad spectrum antibacterial utility are provided by (a) reacting the free amino acid of the appropriate penicillin or cephalosporin or the acid salt or silylated derivative or complex thereof with a reactive derivative of the corresponing N-6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid or (b) reacting the free amino acid 6-aminopenicillanic acid, 7-aminocephalosporanic acid, 7-amino-3-methylceph-3-em-4-carboxylic acid or a related compound or the acid salt or silylated derivative thereof with a reactive derivative of the corresponding D-N-[6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-2-substituted glycine. Pharmaceutical compositions containing said compounds and methods for treating infections using said compositions are also disclosed.

SUMMARY AND DETAILED DESCRIPTION

The present invention relates to novel chemical compounds that areuseful as pharmacological agents and to methods for their production.More particularly, the invention relates to novel organic amidecompounds having the formulae ##STR1## and pharmaceutically-acceptablesalts thereof; wherein R is hydrogen or methyl; R₁ is hydrogen, loweralkyl or hydroxy(lower alkyl), R₂ is hydrogen, lower alkyl,hydroxy(lower alkyl), pyridyl or di(lower alkyl)amino(lower alkyl); R₁R₂ N taken together is 1-pyrrolidinyl, 1-piperidinyl orhydroxymethyl-1-piperidinyl, R₃ is phenyl, 4-hydroxyphenyl, 2-thienyl orcyclohexa-1,4-dien-1-yl; R₄ is hydrogen, acetoxy, a heterocyclicthiogroup where the heterocyclic moiety is an optionally methyl substitutedthiadiazolyl, triazolyl or tetrazolyl group or 1-pyridyl and R₅ ishydrogen or methoxy, with the proviso that when R₄ is 1-pyridyl, the CO₂H is CO₂ ⁻.

The preferred compounds are those wherein R is hydrogen; R₁ and R₂ arehydroxy(lower alkyl). The most preferred compounds are those wherein Ris hydrogen, R₁ and R₂ are hydroxyethyl, R₃ is p-hydroxyphenyl and theR₁ R₂ NSO₂ group is in the para position. The term "lower alkyl" isintended to represent a hydrocarbon moiety of from one to six carbonatoms, such as methyl, ethyl, cyclopropyl, etc.

In accordance with the invention the foregoing amide compounds havingthe formulae ##STR2## and pharmaceutically acceptable salts thereofwherein R, R₁, R₂, R₁ R₂ N, R₃, R₄ and R₅ are as previously defined areproduced by reacting a compound of the formulae ##STR3## or the acidsalt, silylated derivative (preferably the disilylated) or complex(preferably the dimethylsulfoxide) thereof wherein R₃ and R₄ are aspreviously defined, with a reactive derivative of a1,2-dihydro-2-oxonicotinic acid compound having the formula ##STR4## orits acid addition salt, where R, R₁ and R₂ all have the aforementionedsignificance.

Some examples of reactive derivatives of the6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid compoundsuitable for the reaction are the acid halides (especially the acidchloride), the imidazolide, mixed anhydrides (especially those formedfrom an alkyl chloroformate such as ethyl chloroformate and isobutylchloroformate), and activated esters such as the pentachlorophenyl esterand N-hydroxysuccinimide ester.

The reactants are normally employed in approximate equimolar quantities,although an excess of either (oxonicotinic acid compound or amino acidcompound) can be used if desired. The reaction can be carried out in anyof a number of unreactive solvents. When using a silylated derivativefor the reaction the solvent should be anhydrous and may includetertiary amides (such as N,N-dimethylacetamide, dimethylformamide, andN-methyl-2-pyrrolidinone), ethers (such as dioxane, tetrahydrofuran, and1,2-dimethoxyethane), chlorinated hydrocarbons (such as chloroform anddichloromethane), and mixtures of these. In addition to any of thesesolvents, when using the penicillin and cephalosporin type compounds inthe free acid or salt form, aqueous solutions may be used for acylationwith an acid halide or mixed anhydride under normal Schotten-Baumannconditions. The duration and temperature of the reaction are notcritical. Temperatures in the range from -30° to +30° C. are commonlyused for reaction times ranging from a few hours up to a day or more.The product may be isolated in any suitable way as the free acid or as asalt by appropriate adjustment of the pH.

The reactive derivative of6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid compounds andacid-addition salts which are required as starting materials in theforegoing process can be prepared according to any of a variety ofmethods.

A 6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid may beconverted to its acid chloride utilizing thionyl chloride, its mixedanhydride utilizing ethyl chloroformate, its pentachlorophenyl ester byesterification with pentachlorophenol and its imidazolide by reactingthe acid with 1,1'-carbonyldiimidazole.

The silylated amino acid starting materials can be prepared by reactingan amino acid of the formulae ##STR5## or a salt thereof wherein R₃, R₄and R₅ are as previously defined in anhydrous form with either one ortwo equivalents of a tri(lower alkyl)silyl chloride in the presence oftriethylamine. The preferred silylating agents are trimethylsilylchloride and dimethyl dichlorosilane. When two equivalents of thesilylating agent are used, both the amino and the carboxyl group becomesilylated. When one equivalent is used, only the carboxyl group issilylated. Both the mono- and disilylated products are fully reactivewith the activated acids. The disilylated product is preferred over themonosilylated product as a starting material. After acylation the silylgroups are easily removed by treatment with water.

Also in accordance with the invention, the compounds of this inventionmay be produced by reacting a free amino acid of the formulae ##STR6##or the corresponding acid salt or silylated derivative thereof with areactive derivative ofD-N-[6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-2-substitutedglycine having the formula ##STR7## or its acid addition salts where R,R₁, R₂, R₃, R₄ and R₅ have the aforementioned significance.

Some examples of reactive derivatives of theD-N-(1,2-dihydro-2-oxonicotinyl)-2-substituted glycine compoundssuitable for the reaction are the acid halides, the imidazolide, mixedanhydrides (especially those formed from an alkyl chloroformate such asethyl chloroformate and isobutyl chloroformate), and activated esterssuch as the pentachlorophenyl ester and N-hydroxysuccinimide ester.Since racemization is more likely with the acid halide, the other formsare generally preferred. The reactants are normally employed inapproximate equimolar quantities, although an excess of either(oxonicotinic acid compound or amino acid compound) can be used ifdesired. The reaction can be carried out in any of a number ofunreactive solvents. When using the silylated derivative for thereaction the solvent should be anhydrous and may include tertiary amides(such as N,N-dimethylacetamide, dimethylformamide, andN-methyl-2-pyrrolidinone), ethers (such as dioxane, tetrahydrofuran, and1,2-dimethoxyethane), chlorinated hydrocarbons (such as chloroform anddichloromethane), and mixtures of these. In addition to any of thesesolvents, 6-aminopenicillanic acid and 7-amino-3-R₄ CH₂ ceph-3-em-4carboxylic acid may be reacted with an acid chloride or mixed anhydridein the free acid or salt form using aqueous solutions under normalSchotten-Baumann conditions. The duration and temperature of thereaction are not critical. Temperatures in the range from -30° to +30°C. are commonly used for reaction times ranging from a few hours up to aday or more. The product may be isolated in any suitable way as the freeacid or as a salt by appropriate adjustment of the pH.

The reactive derivative ofN-[6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-2-substitutedglycines or their acid-addition salts which are required as startingmaterials in the foregoing process can be prepared by methodsillustrated in greater detail hereinafter.

N-[6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-2-substitutedglycine compounds may be prepared by reacting the corresponding reactivederivative of 6-[(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid,such as acid chloride, with the appropriateD-N-(trimethylsilyl)-2-substituted glycine, trimethylsilyl ester in thepresence of triethylamine followed by hydrolysis.

The silylated amino acid starting materials can be prepared by reactingan anhydrous compound of the formulae ##STR8## with ahexaalkyldisilazane. The preferred silylating agent ishexamethyldisilazane. Only the carboxyl group is silylated under theconditions used (e.g., 2-hour reflux in dichloromethane). Afteracylation, the silyl group is easily removed by treatment with water.

The free acids of the invention form carboxylate salts with any of avariety of inorganic and organic bases. Pharmaceutically-acceptablecarboxylate salts are formed by reacting the free acids with such basesas sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium2-ethylhexanoate, potassium hydroxide, potassium carbonate, potassium2-ethylhexanoate, calcium hydroxide, ethylamine, 2-hydroxyethylamine,and procaine. Preferred carboxylate salt forms are the alkali metalsalts. The carboxylate salts are converted to the free acids byacidification. The free acids and their carboxylate salts usually differsomewhat in solubility properties but, in general, are otherwiseequivalent for the purposes of the invention. In addition, certain ofthe compounds of the invention can exist in the form of an acid-additionsalt, namely where R₂ is pyridyl or di(lower alkyl)amino(lower alkyl).Pharmaceutically-acceptable salts are formed by reaction of the freebase of a carboxylate salt with any of a number of inorganic and organicacids, including hydrochloric, sulfuric, nitric, phosphoric, acetic,benzoic, citric, maleic, malic, tartaric, succinic, gluconic, ascorbic,sulfamic, pamoic, methanesulfonic, benzenesulfonic, and related acids.

The compounds of the invention can exist in anhydrous form, as well asin solvated, including hydrated, forms. In general, the hydrated formsand the solvated forms with pharmaceutically-acceptable solvents areequivalent to the anhydrous or unsolvated forms for the purposes of theinvention.

The compounds of the invention are new chemical compounds that are usedas pharmacological agents and especially as broad spectrum antibacterialagents. They are active in vitro against strains of both gram-positiveand gram-negative bacteria. The activity of the compounds is illustratedby the results shown in the table for certain of the preferredcompounds. The compounds shown in the table are those wherein R ishydrogen and are in the form of their sodium salt.

Thus, the compounds of this invention and their nontoxicpharmaceutically-acceptable salts are highly useful as broad spectrumantibiotics in mammals when administered in amounts ranging from about 5mg. to about 100 mg. per kg. of body weight per day. A preferred dosageregimen for optimum results would be from about 10 mg. to about 50 mg.per kg. of body weight per day, and such dosage units are employed thata total of about 700 mg. to about 3500 mg. of active ingredient for asubject of about 70 kg. body weight are administered in a 24 hour periodin an appropriate pharmaceutical composition.

While the compounds of this invention may be administered orally in theform of tablets, capsules, syrups, etc., the preferred route ofadministration is parenterally for treating systemic infections.

                                      ACTIVITY TABLE                              __________________________________________________________________________                                                Minimal Inhibitory                                                            Concentration, μg/ml.,                                                     vs.:                                                                          Kleb-                                                                         siella        Pseudo-                                                         pneu-                                                                              Ser-                                                                              Enter-                                                                             monas                                                           moniae                                                                             ratia                                                                             obacter                                                                            aerug-                                                    Po-                                                                              Nuc-                                                                             MGH-1                                                                              mar-                                                                              cloacae                                                                            inosa                                                     sition                                                                           leus                                                                             or-2 cescens                                                                           IMM-11                                                                             28 or               R.sub.1       R.sub.2                                                                            R.sub.3                                                                           R.sub.4   R.sub.5                                                                            (a)                                                                              (b)                                                                              (c)  IMM-5                                                                             or-50                                                                              CB-CS               __________________________________________________________________________    HOCH.sub.2 CH.sub.2                                                                         HOCH.sub.2 -                                                                       p-  --        --   p  P   25 (2)                                                                            100 12.5 6.3 (28)                          CH.sub.2                                                                           (HO)-                                                                         C.sub.6 H.sub.4                                            H             H    C.sub.6 H.sub.5                                                                   --        --   m  P  0.8 (1)                                                                            50  1.6                                                                                3.1)                CH.sub.3      H    C.sub.6 H.sub.5                                                                   --        --   p  P  3.1  50  3.1  3.1 (28)            H             H    C.sub.6 H.sub.5                                                                   --        --   p  P  3.1 (2)                                                                            100 6.3  6.3                 CH.sub.3      CH.sub.3                                                                           C.sub.6 H.sub.5                                                                   --        --   p  P  0.8 (1)                                                                            25  1.6                                                                                1.6)                 ##STR9##     H    C.sub.6 H.sub.5                                                                   --        --   p  P  6.3 (1)                                                                            100 6.3                                                                                6.3)                 ##STR10##    H    C.sub.6 H.sub.5                                                                   --        --   p  P  3.1 (1)                                                                            100 3.1                                                                                3.1 (CB-CS)         CH.sub.2CH.sub.2CH.sub.2CH.sub.2                                                                 C.sub.6 H.sub.5                                                                   --        --   p  P  0.8 (2)                                                                            25  3.1  6.3                 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                     C.sub.6 H.sub.5                                                                   --        --   p  P  1.6 (1)                                                                            25  3.1                                                                                3.1 (28)            C.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                                                    C.sub.6 H.sub.5                                                                   --        --   p  P  1.6 (1)                                                                            12.5                                                                              1.6                                                                                0.8)                                                                          (CB-CS)             HOCH.sub.2 CH.sub.2                                                                         HOCH.sub.2 -                                                                       C.sub.6 H.sub.5                                                                   --        --   p  P  1.6 (1)                                                                            100 3.1                                                                                3.1)                              CH.sub.2                                                        CH.sub.3      CH.sub.3                                                                           p-  --        --   p  P  6.3 (2)                                                                            100 6.3  1.6 (28)                               (HO)-                                                                         C.sub.6 H.sub.4                                            HOCH.sub.2 CH.sub.2                                                                         H    C.sub.6 H.sub.5                                                                   --        --   p  P  6.3 (2)                                                                            100 6.3  6.3 (28)             ##STR11##         C.sub.6 H.sub.5                                                                   --        --   p  P  6.3 (2)                                                                            50  3.1                                                                                12.5 (28)           (CH.sub.3).sub.2 N(CH.sub.2).sub.2                                                          H    C.sub.6 H.sub.5                                                                   --        --   p  P  12.5 (2)                                                                           200 6.3  6.3 (28)            (CH.sub.3).sub.2 N(CH.sub.2).sub.2                                                          H    p-  --        --   p  P  3.1 (2)                                                                            --  1.6                                                                                0.8 (28)                               (HO)-                                                                         C.sub.6 H.sub.5                                            CH.sub.3      H    C.sub.6 H.sub.5                                                                   CH.sub.3 CO.sub.2                                                                       H    p  C  6.3 (1)                                                                            200 6.3                                                                                25 (28)             HOCH.sub.2 CH.sub.2                                                                         HOCH.sub.2 -                                                                       C.sub.6 H.sub.5                                                                   CH.sub.3 CO.sub.2                                                                       H    p  C  1.6 (2)                                                                            200 6.3                                                                                12.5                              CH.sub.2                                                        CH.sub.3      CH.sub.3                                                                           C.sub.6 H.sub.5                                                                   CH.sub.3 CO.sub.2                                                                       CH.sub.3 O                                                                         p  C  6.3 (2)                                                                            200 12.5                                                                               --1)                CH.sub.3      CH.sub.3                                                                           C.sub.6 H.sub.5                                                                    ##STR12##                                                                              H    p  C  0.4 (2)                                                                            25  0.8                                                                                6.3 (28)            CH.sub.3      CH.sub.3                                                                           C.sub.6 H.sub.5                                                                   CH.sub.3 CO.sub.2                                                                       H    p  C  3.1  200 6.3  6.3                                                                           (CB-CS)             HOCH.sub.2 CH.sub.2                                                                         HOCH.sub.2 - CH.sub.2                                                              C.sub.6 H.sub.5                                                                    ##STR13##                                                                              H    p  C  0.8  --  3.1  12.5                __________________________________________________________________________     (a) Shows the position of the R.sub.1 R.sub.2 NSO.sub.2 group on the          phenyl ring.                                                                  (b) Nucleus indicates if the group are on a penicillin (P) or a               cephalosporin (C) nucleus.                                                    (c) Where strain is not designated, the M.I.C. value applies to both.    

In the present invention the term "pharmaceutical composition" isdefined as a finished pharmaceutical that may be administered directlyor a pharmaceutical which water is added to prior to use in order toform a satisfactory product for administration. The pharmaceuticalcompositions to be employed parenterally are generally supplied in adry, sterile form having about 50 mg. to about 1000 mg. of activecompound per vial. The vial may also contain other active ingredients,buffers, salts, etc. The sterile material in the vial is dissolved inwater for injection at the time of use. Oral preparations would alsohave from about 50 mg. to about 1000 mg. of active compound per unitdose form.

The invention is illustrated by the following examples.

EXAMPLE 1

6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester, 20 g. is added to a stirredmixture of 25.5 g. of an amoxicillindimethyl sulfoxide complex and 400ml. of dimethyl sulfoxide, cooled in an ice bath. The mixture is stirredat room temperature for 4 hours and the resulting solution is pouredinto 500 ml. of ice water and acidified to pH 2.0 with dilutehydrochloric acid. The resulting precipitate ofN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillinis collected by filtration and washed thoroughly with cold water. Thesolid is suspended in 400 ml. of cold water and the pH is brought to 6.0with 1N aqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to giveN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillin,sodium salt; [α]_(D) ²³ = +146° (1.0% in methanol); iodometric assay,95.6%.

EXAMPLE 2

A stirred suspension of 3.97 g. of the triethylamine salt of ampicillin(U.S. Pat. No. 3,954,734) in 60 ml. of N,N-dimethylacetamide is cooledto 0°-5° C. and treated in turn with 2.23 ml. of trimethylsilyl chlorideand 1.24 ml. of triethylamine. The mixture is stirred at roomtemperature for 1 hour, then cooled to 0°-5° and treated in turn with1.24 ml. of triethylamine and 2.76 g. of6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride. Themixture is stirred at 0°-5° C. for 30 minutes, then at room temperaturefor 16 hours. The mixture is poured into 200 ml. of ice water and the pHis adjusted to 2.0 with dilute hydrochloric acid. The resultingprecipitate ofN-[6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin iscollected by filtration, washed with water and dried. The solid issuspended in 75 ml. of cold water and the pH is brought to 8.0 with 2Naqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to giveN-[6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt; [α]_(D) ²³ = +131° (0.99% in methanol); iodometric assay,80.9%.

EXAMPLE 3

A stirred suspension of 7.28 g. of the triethylamine salt of ampicillinin 120 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 4.1 ml. of trimethylsilyl chloride and 2.26 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated in turn with 5.29 g. of6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chlorideand 2.26 ml. of triethylamine. The mixture is stirred at 0°-5° C. for 30minutes, then at room temperature for 16 hours. The mixture is pouredinto 400 ml. of ice water and the pH is adjusted to 2.1 with dilutehydrochloric acid. The resulting precipitate ofN-[6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration, washed with water and dried. The solid isdissolved in 75 ml. of tetrahydrofuran and 8.5 ml. of 50% sodium2-ethylhexanoate in n-butanol is added to the solution. The resultingmixture is diluted with 150 ml. of ether and the precipitatedN-[6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt removed by filtration, washed with ether and dried; [α]_(D)²³ = +141° (1.02% in methanol); iodometric assay, 81.8%.

EXAMPLE 4

A stirred suspension of 5.89 g. of the triethylamine salt of ampicillinin 100 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 3.31 ml. of trimethylsilyl chloride and 1.83 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated in turn with 1.83 ml. oftriethylamine and 4.1 g. of6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride. Themixture is stirred at 0°-5° C. for 30 minutes, then at room temperaturefor 16 hours. The mixture is poured into 300 ml. of ice water and the pHis adjusted to 2.1 with dilute hydrochloric acid. The resultingprecipitate ofN-[6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin iscollected by filtration, washed with water and dried. The solid isdissolved in 50 ml. of tetrahydrofuran and 5.0 ml. of 50% sodium2-ethylhexanoate in n-butanol is added to the solution. The resultingmixture is diluted with 150 ml. of ether and the precipitatedN-[6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt removed by filtration, washed with ether and dried; [α]_(D)²³ = +142° (1.03% in methanol); iodometric assay, 73.9%.

EXAMPLE 5

A stirred suspension of 4.9 g. of the triethylamine salt of ampicillinin 100 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 2.75 l ml. of trimethylsilyl chloride and 1.55 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated in turn with 1.55 ml. oftriethylamine and 3.71 g. of6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.The mixture is stirred at 0°-5° C. for 30 minutes, then at roomtemperature for 16 hours. The mixture is poured into 300 ml. of icewater and the pH is adjusted to 2.0 with dilute hydrochloric acid. Theresulting precipitate ofN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration, washed with water and dried. The solid isdissolved in 75 ml. of N,N-dimethylacetamide and 3.8 ml. of 50% sodium2-ethylhexanoate in n-butanol is added to the solution. The resultingsolution is poured into 250 ml. of ethyl acetate. The precipitatedN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt is collected by filtration, washed with ethyl acetate anddried; [α]_(D) ²³ = +152° (1.0% in methanol); iodometric assay, 90.2%.

EXAMPLE 6

A stirred suspension of 4.85 g. of the triethylamine salt of ampicillinin 100 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 1.5 ml. of triethylamine and 2.75 ml. of trimethylsilylchloride. The mixture is stirred at room temperature for 1 hour, thencooled to 0°-5° C. and treated in turn with 3.0 ml. of triethylamine and4.6 g. of6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloridehydrochloride. The mixture is stirred at 0°-5° C. for thirty minutes,then at room temperature for 16 hours. The mixture is poured into 300ml. of ice water and the pH is adjusted to 3.0 with dilute hydrochloricacid. The resulting precipitate ofN-[6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration, washed with water and dried. The solid isdissolved in 100 ml. of N,N-dimethylacetamide and 2.5 ml. of 50% sodium2-ethylhexanoate in n-butanol is added to the solution. The resultingsolution is poured into 300 ml. of ethyl acetate. The precipitatedN-[6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt is collected, washed with ethyl acetate and dried; [α]_(D)²³ = +110° (1.04% in methanol); iodometric assay, 67%.

EXAMPLE 7

By substituting 4.6 g. of6-[4-(2-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloridehydrochloride for the6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloridehydrochloride in Example 6, there is obtained the sodium salt ofN-[6-[4-(2-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin;[α]_(D) ²³ = +174° (1.02% in methanol); iodometric assay 75.7%.

EXAMPLE 8

A stirred suspension of 5.17 g. of the triethylamine salt of ampicillinin 100 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 2.91 ml. of trimethylsilyl chloride and 1.61 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated in turn with 1.61 ml. oftriethylamine and 4.22 g. of6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylchloride. The mixture is stirred at 0°-5° C. for thirty minutes, then atroom temperature for 16 hours. The mixture is poured into 300 ml. of icewater and the pH is adjusted to 2.5 with dilute hydrochloric acid. Theresulting precipitate ofN-[6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration, washed well with water and dried. The solidis dissolved in 100 ml. of N,N-dimethylacetamide and 3.7 ml. of 50%sodium 2-ethylhexanoate in n-butanol is added to the solution. Theresulting solution is poured into 300 ml. of ethyl acetate. TheN-[6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt is collected, washed with ethyl acetate and dried; [α]_(D)²³ = +147° (1.02% in methanol); iodometric assay, 90.2%.

EXAMPLE 9

A stirred suspension of 6.2 g. of the triethylamine salt of ampicillinin 150 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 3.5 ml. of trimethylsilyl chloride and 2.0 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated in turn with 2.0 ml. oftriethylamine and 5.26 g. of6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.The mixture is stirred at 0°-5° C. for 30 minutes, then at roomtemperature for 16 hours. The mixture is poured into 400 ml. of icewater and the pH is adjusted to 2.0 with dilute hydrochloric acid. Theresulting precipitate ofN-[6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration, washed well with water and dried. The solidis dissolved in 100 ml. of methylene chloride and 4.5 ml. of 50% sodium2-ethylhexanoate in n-butanol is added to the solution. The resultingsolution is diluted with 400 ml. of ethyl acetate. The precipitatedN-[6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt is collected by filtration, washed with ethyl acetate anddried; [α]_(D) ²³ = +124° (1.02% in methanol); iodometric assay, 82.8%.

EXAMPLE 10

A stirred suspension of 7.7 g. of the triethylamine salt of ampicillinin 200 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 4.35 ml. of trimethylsilyl chloride and 2.4 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated in turn with 2.4 ml. oftriethylamine and 6.3 g. of6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.The mixture is stirred at 0°-5° C. for 30 minutes, then at roomtemperature for 16 hours. The mixture is poured into 500 ml. of icewater and the pH is adjusted to 2.0 with dilute hydrochloric acid. Theresulting precipitate ofN-[6-[4-diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration, washed well with water and dried. The solidis dissolved in 100 ml. of N,N-dimethylacetamide and 5.0 ml. of 50%sodium 2-ethylhexanoate in n-butanol is added to the solution. Theresulting solution is poured into 400 ml. of ethyl acetate. TheprecipitatedN-[6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt is collected, washed with ethyl acetate and dried; [α].sub.D²³ = +150° (1.0% in methanol; iodometric assay, 92.2%.

EXAMPLE 11

A stirred suspension of 28.1 g. of the triethylamine salt of ampicillinin 500 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 15.8 ml. of trimethylsilyl chloride and 8.72 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated with 30.0 g. of6-[4-[bis-(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester. The mixture is stirred at 0°-5° C.for 30 minutes, then at room temperature for 16 hours. The mixture ispoured into 1 1. of ice water and the ph is adjusted to 2.0 with dilutehydrochloric acid. The resulting precipitate ofN-[6-[4-[bis-(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration and washed well with cold water. The solid issuspended in 400 ml. of cold water and the pH is brought to 7.5 with 1Naqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to giveN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt; [α]_(D) ²³ = +148° (1.0% in methanol); iodometric assay,94.9%.

EXAMPLE 12

A stirred solution of 13.2 g. of an amoxicillin-dimethyl sulfoxidecomplex in 200 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. andtreated in turn with 7.5 g. of6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylimidazolide and 2.7 ml. of triethylamine. The solution is stirred atroom temperature for 6 hours, then clarified by filtration and pouredinto 500 ml. of ice water acidified with 20 ml. of 1N hydrochloric acid.The pH of the mixture is adjusted to 3.0 with dilute hydrochloric acidand the resulting precipitate ofN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillinis collected by filtration and washed well with water. The solid issuspended in 350 ml. of cold water and the pH is brought to 6.7 with 1Naqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to giveN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillin,sodium salt; [α]_(D) ²³ = +180° (1.0% in 75%dimethylformamide/pyridine); iodometric assay, 86%.

EXAMPLE 13

A stirred suspension of 3.73 g. of the triethylamine salt of ampicillinin 50 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 2.1 ml. of trimethylsilyl chloride and 1.16 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated with 3.61 g. of6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester. The mixture is stirred at 0°-5° C.for 30 minutes, then at room temperature for 16 hours. The mixture ispoured into 200 ml. of ice water and the pH is adjusted to 2.0 withdilute hydrochloric acid. The resulting precipitate ofN-[6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration and washed well with water. The solid issuspended in 75 ml. of cold water and the pH is brought to 7.5 with 1Naqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to give the sodium salt. This sodium salt isdissolved in 50 ml. of cold methanol. The solution is diluted withsufficient 2-propanol to precipitate the sodium salt, which is collectedby filtration and then dissolved in 80 ml. of cold water. The aqueoussolution is freeze-dried to give the purifiedN-[6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt; [α]_(D) ²³ = +157° (1.03% in methanol); iodometric assay,95.1%.

EXAMPLE 14

A stirred suspension of 3.4 g. of the triethylamine salt of ampicillinin 50 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 1.91 ml. of trimethylsilyl chloride and 1.05 ml. oftriethylamine. The mixture is stirred at room temperature for 1 hour,then cooled to 0°-5° C. and treated with 3.7 g. of6-[4-[(3-hydroxymethyl-1-piperidinyl)sulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester. The mixture is stirred at 0°-5° C.for 30 minutes, then at room temperature for 16 hours. The mixture ispoured into 200 ml. of ice water and the pH is adjusted to 2.0 withdilute hydrochloric acid. The resulting precipitate ofN-[6-[4-[(3-hydroxymethyl-1-piperidinyl)sulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration and washed well with water. The solid issuspended in 75 ml. of cold water and the pH is brought to 7.5 with 1Naqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to giveN-[6-[4-[(3-hydroxymethyl-1-piperidinyl)sulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt; [α]_(D) ²³ = +140° (1.01% in methanol); iodometric assay,93.2%.

EXAMPLE 15

A stirred suspension of 4.31 g. of the triethylamine salt of ampicillinin 60 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 2.67 ml. of triethylamine and 4.03 g. of6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinylchloride hydrochloride. The mixture is stirred at 0°-5° C. for 30minutes, then at room temperature for 16 hours. The mixture is filteredand the filtrate is poured into a mixture of 150 ml. of ethyl acetateand 150 ml. of ether. The precipitated solid is collected by filtration,washed with ether and dried. The solid is suspended in 75 ml. of coldwater and the pH is brought to 7.8 with 1N aqueous sodium hydroxide. Theresulting solution is clarified by filtration and freeze-dried to giveN-[6-[4-[(dimethylaminoethyl)aminosulfonyl]phenyl]1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt; [α]_(D) ²³ = +121° (1.02% in 50% methanol/pH7 phosphatebuffer); iodometric assay, 69.9%.

EXAMPLE 16

A stirred solution of 5.73 g. of an amoxicillin-dimethyl sulfoxidecomplex in 80 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. andtreated in turn with 3.97 ml. of triethylamine and 4.0 g. of6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinylchloride hydrochloride. The mixture is stirred at 0°-5° C. for 30minutes, then at room temperature for 16 hours. The mixture is filteredto remove triethylamine hydrochloride and the filtrate is poured into300 ml. of ethyl acetate. The precipitated solid is collected byfiltration, washed with ethyl acetate and dried. The solid is suspendedin 75 ml. of cold water and the pH is brought to 8.4 with 1N aqueoussodium hydroxide. The resulting solution is clarified by filtration andfreeze-dried to giveN-[6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillin,sodium salt; [α]_(D) ²³ = +123° (1.03% in 75%dimethylformamide/pyridine); iodometric assay, 71.8%.

EXAMPLE 17

A stirred suspension of 2.02 g. of cephaloglycin hemihydrate in 50 ml.of N,N-dimethylacetamide is cooled to 0°-5° C. and treated in turn with1.7 ml. of triethylamine and 1.54 ml. of trimethylsilyl chloride. Themixture is stirred at room temperature for 1 hour, then cooled to 0°-5°C. and treated in turn with 0.68 ml. of triethylamine and 1.59 g. of6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.The mixture is stirred at 0°-5° C. for 30 minutes, then at roomtemperature for 16 hours. The mixture is poured into 200 ml. of icewater and the pH is adjusted to 2.1 with dilute hydrochloric acid. Theresulting precipitate ofN-[6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]cephaloglycinis collected by filtration, washed well with water and dried. The solidis suspended in 100 ml. of 50% tetrahydrofuran/dimethylformamide and themixture is treated with 5.0 ml. of 50% sodium 2-ethylhexanoate inn-butanol. The resulting solution is poured into 200 ml. of ether andthe precipitatedN-[6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]cephaloglycin,sodium salt is collected by filtration, washed with ether and dried;[α]_(D) ²³ = +69° (1.02% in methanol); chromatography indicates a purityof 94%.

EXAMPLE 18

By substituting 2.3 g. of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo1-pyrrolidinyl ester, for the6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride inExample 17, there is obtainedN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]cephaloglycin.This solid is suspended in 50 ml. of cold water and the pH is brought to7.5 with 1N aqueous sodium hydroxide. The solution is clarified byfiltration and freeze-dried to giveN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]cephaloglycin,sodium salt; [α]_(D) ²³ = +70°; chromatography indicates a purity of99%.

EXAMPLE 19

A stirred suspension of 2.2 g. of 7-α-methoxycephaloglycin (Brit. Pat.No. 1,348,984) in 30 ml. of N,N-dimethylacetamide is cooled to 0°-5° C.and treated in turn with 1.05 ml. of trimethylsilyl chloride and 1.2 ml.of triethylamine. The mixture is stirred at 0°-5° C. for 10 minutes,then treated in turn with 1.4 g. of6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chlorideand 0.56 ml. of triethylamine. The mixture is stirred for 1 hour at 5°C., filtered and the filtrate treated with 5.0 ml. of 50% sodium2-ethylhexanoate in n-butanol. The resulting solution is diluted with100 ml. of ethyl acetate. The precipitate ofN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-7-.alpha.-methoxycephaloglycin,sodium salt is collected by filtration, washed with ethyl acetate anddried; [α]_(D) ²³ = +42.5° (0.99% in pH 7 phosphate buffer);chromatography indicates a purity of 85.5%.

EXAMPLE 20

A stirred solution of 5.2 g. of the sodium salt of3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-(D-α-amino-.alpha.-phenylacetamido)-3-cephem-4-carboxylicacid (U.S. Pat. No. 3,954,734) in 60 ml. of N,N-dimethylacetamide iscooled to 0°-5° C. and treated in turn with 3.04 g. of6-[4-(dimethylaminosulfonyl)phenyl°-1,2-dihydro-2-oxonicotinyl chlorideand 1.37 ml. of triethylamine. The mixture is stirred for 3 hours at0°-5° C., then poured into 200 ml. of ice water. The pH is adjusted to3.0 with dilute hydrochloric acid and the resulting precipitate of3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-[D-α-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinamido]-α-phenylacetamido]-3-cephem-4-carboxylicacid is collected by filtration and washed well with water. The solid issuspended in 400 ml. of ice water and the pH is brought to 8.0 with 1Naqueous sodium hydroxide. The solution is clarified by filtration andfreeze-dried to give the3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-[D-α-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinamido]-α-phenylacetamido]-3-cephem-4-carboxylicacid, sodium salt; [α]_(D) ²³ = -36° (1.0% in methanol); chromatographyindicates a purity of 78%.

EXAMPLE 21

By substituting 1.7 g. of6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloridefor the 6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylchloride in Example 17, there is obtainedN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]cephaloglycin,sodium salt; [α]_(D) ²³ = +71° (1.04% in 75% dimethylformamide/pyridine;chromatography indicates a purity of 90%.

EXAMPLE 22

A stirred solution of 5.2 g. of the sodium salt of3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-(D-α-amino-.alpha.-phenyl-acetamido)-3-cephem-4-carboxylicacid in 70 ml. of N,N-dimethyl-acetamide is cooled to 0°-5° and treatedwith 4.8 g. of6-[4-[bis-(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester. The mixture is stirred at 0°-5° C.for 2.5 hours, then at room temperature for 16 hours. The resultingsolution is poured into 250 ml. of ethyl acetate and the precipitatedsolid collected by filtration, washed with ethyl acetate and dried. Thesolid is dissolved in 200 ml. of ice water and the pH is adjusted to 2.0with dilute hydrochloric acid. The resulting precipitate of3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxo-nicotinamido]-.alpha.-phenylacetamido]-3-cephem-4-carboxylicacid is collected by filtration and washed well with cold water. Thesolid is suspended in 500 ml. of cold water and the pH brought to 7.7with 1N aqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to give 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-phenylacetamido]-3-cephem-4-carboxylicacid, sodium salt; [α]_(D) ²³ = -8° (1% in methanol); chromatographyindicates a purity of 77%.

EXAMPLE 23

By substituting 15.2 g. of epicillin hemihydrate for theamoxicillin-dimethyl sulfoxide complex in Example 1, there is obtainedN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]epicillin,sodium salt.

EXAMPLE 24

By substituting 1.79 g. of cephalexin monohydrate for the cephaloglycinhemihydrate in Example 17, there is obtainedN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]cephalexin,sodium salt.

EXAMPLE 25

By substituting an equivalent amount of the sodium salt of theappropriate3-[[heterocyclic)thio]methyl]-7-(D-α-amino-α-phenylacetamido)-3-cephem-4-carboxylicacid [J. Antibiotics, 29, 65-80 (1976)] for the sodium salt of3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-(D-α-amino-.alpha.-phenylacetamido)-3-cephem-4-carboxylicacid in Example 22, the following products are obtained:

(a)3-[[(1,2,3-triazol-5-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-phenylacetamido]-3-cephem-4-carboxylicacid, sodium salt.

(b)3-[[(1,2,3-triazol-5-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-(4-hydroxyphenyl)acetamido]-3-cephem-4-carboxylicacid, sodium salt.

(c)3-[[(1-methyl-1,2,3,4-tetrazol-5-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido-α-phenylacetamido]-3-cephem-4-carboxylicacid, sodium salt.

(d)3-[[(1-methyl-1,2,3,4-tetrazol-5-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-(4-hydroxyphenyl)acetamido]-3-cephem-4-carboxylicacid, sodium salt.

(e)3-[[(1-methyl-1,2,3-triazol-5-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-phenylacetamido]-3-cephem-4-carboxylicacid, sodium salt.

(f)3-[[(4-methyl-1,2,3-triazol-5-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-phenylacetamido]-3-cephem-4-carboxylicacid, sodium salt.

(g)3-[[(5-methyl-4,1,2-triazol-3-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-phenylacetamido]-3-cephem-4-carboxylicacid, sodium salt.

(h)3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-[D-α-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinamido]-α-(4-hydroxyphenyl)acetamido]-3-cephem-4-carboxylicacid, sodium salt.

EXAMPLE 26

A stirred solution of 4.55 g. ofD-N-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-2-phenylglycinein 50 ml. of N,N-dimethylacetamide is cooled to 0°-5° C. and treated inturn with 1.4 ml. of triethylamine and 0.96 ml. of ethyl chloroformate.The mixture is stirred for 15 minutes at 0°-5° C., then treated with 25ml. of a 0.44M solution of 6-aminopenicillanic acid, trimethylsilylester [Glombitza, Ann. 673,166 (1964)]. The mixture is stirred at 0°-5°C. for 1 hour, then at room temperature for 2 hours. The mixture ispoured into 200 ml. of ice water and the pH is adjusted to 2.0 withdilute hydrochloric acid. The resulting precipitate ofN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinis collected by filtration and washed well with cold water. The solid issuspended in 200 ml. of cold water and the pH is brought to 7.5 with 1Naqueous sodium hydroxide. The resulting solution is clarified byfiltration and freeze-dried to giveN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt; [α ]_(D) ²³ = +152° (1% in methanol).

EXAMPLE 27

By substituting 20 g. of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester for the 20 g. of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester of Example 1, there is obtainedN-[6-[4-bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinyl]amoxicillin,sodium salt.

EXAMPLE 28

By substituting 14.2 g. of6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinylchloride for the 20 g. of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester of Example 1, there is obtainedN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinyl]amoxicillin,sodium salt.

STARTING MATERIALS AND INTERMEDIATES A. Amoxicillin-Dimethyl SulfoxideComplex

Fifty grams of amoxicillin trihydrate is added in portions, withstirring, to 375 ml. of dimethyl sulfoxide. The mixture is stirred atroom temperature for 2 hours, then diluted with 75 ml. of methylenechloride and cooled to 0°-5°. The solid product is collected byfiltration, washed with methylene chloride and dried. Analysis shows 3moles of dimethyl sulfoxide and 0.5 mole of water for each mole ofamoxicillin; formula weight = 609.

B. 4-Acetylbenzenesulfonyl Chloride

A suspension of 100 g. of sodium 4-acetylbenzenesulfonate in 225 ml. ofdimethylformamide is treated with 31 ml. of thionyl chloride and themixture is stirred at room temperature for 5 minutes, then poured into 1l. of ice water. The resulting precipitate of 4-acetylbenzenesulfonylchloride is collected by filtration and washed with ice water. Thestill-damp product may be used as such without further purification.However, if purification is desired, the following procedure may beused: The product is dissolved in methylene chloride and the solution isdried and evaporated at reduced pressure. Th residual sulfonyl chlorideis crystallized from benzene/hexane; m.p. 83°-85° C.

C. 4-Acetylbenzenesulfonamides (a)4-Acetyl-N,N-bis(2-hydroxyethyl)benzenesulfonamide

The damp 4-acetylbenzenesulfonyl chloride from 300 g. of sodium4-acetylbenzenesulfonate is added in portions to a well-stirred, cooledsolution of 500 ml. of bis(2-hydroxyethyl)amine in 750 ml. of water. Themixture is stirred at room temperature for 16 hours, cooled to 0°-5° C.and the precipitate of4-acetyl-N,N-bis(2-hydroxyethyl)benzenesulfonamide is collected byfiltration and crystallized from water; m.p. 87.5°-89.5° C.

(b) 4-Acetyl-N-methylbenzenesulfonamide

The damp 4-acetylbenzenesulfonyl chloride from 50 g. of sodium4-acetylbenzenesulfonate is added in portions, with stirring, to 500 ml.of cold 40% aqueous methylamine. The mixture is stirred at roomtemperature for 16 hours, then cooled and the precipitate collected byfiltration. The solid (which proved to be the N-methylimine derivativeof the ketosulfonamide) is dissolved in 300 ml. of 6% hydrochloric acidand the solution is heated at 80°-90° C. for 30 minutes, then cooled.The resulting precipitate of 4-acetyl-N-methylbenzenesulfonamide iscollected by filtration and crystallized from aqueous ethanol; m.p.107°-109° C.

(c) 4-Acetylbenzenesulfonamide

The damp 4-acetylbenzenesulfonyl chloride from 50 g. of sodium4-acetylbenzenesulfonate is added in portions, with stirring, to 500 ml.of concentrated aqueous ammonia. The mixture is stirred at roomtemperature for 16 hours, cooled, and the precipitated4-acetylbenzenesulfonamide removed by filtration and crystallized fromaqueous ethanol/acetone; m.p. 177°-179° C.

(d) 4-Acetyl-N,N-dimethylbenzenesulfonamide

From the damp 4-acetylbenzenesulfonyl chloride from 200 g. of sodium4-acetylbenzenesulfonate, and 1 l. of 20% aqueous dimethylamine,following the procedure of (c) above, there is obtained4-acetyl-N,N-dimethylbenzenesulfonamide; m.p. 97°-99° C. aftercrystallization from aqueous ethanol.

(e) 4-Acetyl-N-(3-pyridyl)benzenesulfonamide

To a solution of 23.7 g. of 3-aminopyridine in 400 ml. of pyridine isadded 55 g. of 4-acetylbenzenesulfonyl chloride and the resultingsolution is stirred at room temperature for 24 hours. The solution ispoured into 1 l. of water and the mixture is cooled to 0°-5° C. Theprecipitate of 4-acetyl-N-(3-pyridyl)benzenesulfonamide is collected byfiltration, washed with water and dried; m.p. 182°-183° aftercrystallization from ethanol.

(f) 4-Acetyl-N-(2-pyridyl)benzenesulfonamide

A solution of 13.4 g. of 2-aminopyridine in 300 ml. of pyridine istreated with 31.0 g. of 4-acetylbenzenesulfonyl chloride and thesolution is stirred at room temperature for 6 hours. The solution ispoured into 1 l. of cold water and the resulting precipitate of4-acetyl-N-(2-pyridyl)benzensulfonamide is collected by filtration,washed with water and dried; m.p. 201°-202° C. after crystallizationfrom methanol.

(g) 1-(4-Acetylbenzenesulfonyl)pyrrolidine

A solution of 500 ml. of 50% aqueous pyrrolidine is treated in portionswith 30.0 g. of 4-acetylbenzenesulfonyl chloride and the solution isstirred at room temperature for 1 hour. The resulting mixture is cooledto 0°-5° C. and the precipitated 1-(4-acetylbenzenesulfonyl)pyrrolidineis collected by filtration, washed with water and dried; m.p. 138°-139°C. after crystallizations from aqueous methanol and from 2-propanol.

(h) 1-(4-Acetylbenzenesulfonyl)piperidine

The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of50% aqueous piperidine. The mixture is stirred at room temperature for16 hours, cooled, and the precipitated1-(4-acetylbenzenesulfonyl)piperidine removed by filtration, washed withwater and dried; m.p. 113°-114° C. after crystallization from2-propanol.

(i) 4-Acetyl-N,N-diethylbenzenesulfonamide

The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of50% aqueous diethylamine. The mixture is stirred at room temperature for4 hours, cooled, and the precipitated4-acetyl-N,N-diethylbenzenesulfonamide removed fy filtration, washedwith water and dried; m.p. 78°-79° C. after crystallization from2-propanol.

(j) 4-Acetyl-N-(2-hydroxyethyl)benzenesulfonamide

The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of50% aqueous 2-hydroxyethylamine. The mixture is stirred at roomtemperature for 16 hours, then acidified with hydrochloric acid andcooled to 0°-5° C. The precipitate of4-acetyl-N-(2-hydroxyethyl)benzenesulfonamide is collected byfiltration, washed with water and dried; m.p. 119°-121° C. aftercrystallization from water.

(k) 1-(4-Acetylbenzenesulfonyl)-3-piperidinemethanol

The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium4-acetylbenzenesulfonate is added to a solution of 114 g. of3-piperidinemethanol in 900 ml. of water. The mixture is stirred at roomtemperature for 16 hours, cooled, and the precipitate for1-(4-acetylbenzenesulfonyl)-3-piperidinemethanol collected byfiltration, washed with water and dried; m.p. 104°-106° C. aftercrystallization from aqueous ethanol.

(l) 4-Acetyl-N-(2-dimethylaminoethyl)benzenesulfonamide

The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium4-acetylbenzenesulfonate is added to a solution of 83 g. ofN,N-dimethylethylenediamine in 730 ml. of water. The mixture is stirredat room temperature for 16 hours, cooled, and the precipitate of4-acetyl-N-(2-dimethylaminoethyl)benzenesulfonamide collected byfiltration, washed with water and dried; m.p. 87°-89° C. aftercrystallization from 2-propanol/hexane.

D. 6-(Substituted-phenyl)-1,2-dihydro-2-oxonicotinonitriles (a)6-[4-[Bis(2-hydroxyethyl)aminosulfonyl]phenyl-1,2-dihydro-2-oxonicotinonitrile

A stirred suspension of 117.7 g. of sodium methoxide in 1 l. oftetrahydrofuran under a nitrogen atmosphere is cooled to 0°-5° C. andtreated with 178 ml. of ethyl formate. The cold mixture is then treateddropwise, with stirring, with a solution of 190.1 g. of4-acetyl-N,N-bis(2-hydroxyethyl)benzenesulfonamide in 1.75 l. oftetrahydrofuran, then stirred at room temperature for 16 hours. Themixture is diluted with 500 ml. of ether and the resulting precipitateof the sodium salt of4-[bis(2-hydroxyethyl)aminosulfonyl]benzoylacetaldehyde is collected byfiltration, washed with ether and dried. A solution of this sodium saltin 2.5 l. of water is adjusted to pH 9 with acetic acid and 84 g. ofcyanoacetamide is added. The solution is heated at 90° for 6 hours, thenallowed to stand at room temperature for 16 hours. The mixture isacidified to pH 6 with acetic acid and cooled to 0°-5°. The resultingprecipitate of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinonitrileis collected by filtration, washed with water and dried; m.p. 226°-228°C. after crystallization from aqueous methanol/dimethylformamide.

In a similar manner, the following nitriles are prepared:

(b) 6-[3-(Aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinitrile

From a solution of the sodium salt of3-(aminosulfonyl)benzoylacetaldehyde in 1 l. of water (prepared from20.5 g. of sodium methoxide in 500 ml. of tetrahydrofuran, 31 ml. ofethyl formate, and a solution of 34.0 g. of 3-acetylbenzenesulfonamide[J. prakt. Chem., 22, 192 (1963)] in 500 ml. of tetrahydrofuran) and21.8 g. of cyanoacetamide, there is obtained6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p.271°-274° C. (dec.) after digestion with ethyl acetate.

(c) 6-[4-(Methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(methylaminosulfonyl)benzoylacetaldehyde in 1 l. of water (preparedfrom 25.3 g. of sodium methoxide in 500 ml. of tetrahydrofuran, 38.2 ml.of ethyl formate, and a solution of 45.4 g. of4-acetyl-N-methylbenzenesulfonamide in 700 ml. of tetrahydrofuran) and26.8 g. of cyanoacetamide, there is obtained6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p.282°-286° C. (dec.) after crystallization from aqueousdimethylformamide.

(d) 6-[4-(Aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(aminosulfonyl)benzoylacetaldehyde in 1.5 l. of water (prepared from28.6 g. of sodium methoxide in 500 ml. of tetrahydrofuran, 43 ml. ofethyl formate, and a solution of 48 g. of 4-acetylbenzenesulfonamide in1 l. of tetrahydrofuran) and 30.2 g. of cyanoacetamide, there isobtained 6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 267°-268° C. (dec.) after digestion with hot ethyl acetate.

(e) 6-[4-(Dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(dimethylaminosulfonyl)benzoylacetaldehyde in 2 l. of water (preparedfrom 36.1 g. of sodium methoxide in 500 ml. of tetrahydrofuran, 49.5 g.of ethyl formate, and a solution of 137.8 g. of4-acetyl-N,N-dimethylbenzenesulfonamide in 1.4 l. of tetrahydrofuran)and 76.6 g. of cyanoacetamide, there is obtained6-[4-dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 263°-267° C. (dec.) after crystallization from aqueousdimethylformamide.

(f)6-[4-(2-Pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(3-pyridylaminosulfonyl)benzoylacetaldehyde in 1 l. of water (preparedfrom 17.3 g. of sodium methoxide in 300 ml. of tetrahydrofuran, 26 ml.of ethyl formate, and a solution of 42 g. of4-acetyl-N-(3-pyridyl)benzenesulfonamide in 1 l. of tetrahydrofuran) and19.2 g. of cyanoacetamide, there is obtained6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 237°-239° C. after digestion with warm methanol and with warm ethylacetate.

(g)6-[4-(2-Pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(3-pyridylaminosulfonyl)benzoylacetaldehyde in 400 ml. of water(prepared from 7.85 g. of sodium methoxide in 400 ml. oftetrahydrofuran, 11.8 ml. of ethyl formate, and a solution of 19.0 g. of4-acetyl-N-(2-pyridyl)benzenesulfonamide in 400 ml. of tetrahydrofuran)and 8.75 g. of cyanoacetamide, there is obtained6-[4-(2-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 254°-255° C. after crystallization from aqueousethanol/dimethylformamide.

(h)6-[4-(1-Pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(1-pyrrolidinylsulfonyl)benzoylacetaldehyde in 400 ml. of water(prepared from 3.82 g. of sodium methoxide in 200 ml. oftetrahydrofuran, 5.8 ml. of ethyl formate, and a solution of 16.3 g. of1-(4-acetylbenzenesulfonyl)pyrrolidine in 200 ml. of tetrahydrofuran)and 8.2 g. of cyanoacetamide, there is obtained6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 298°-301° C. (dec.) after crystallization from aqueousdimethylformamide.

(i) 6-[4-(1-Piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(1-piperidinylsulfonyl)benzoylacetaldehyde in 400 ml. of water(prepared from 8.9 g. of sodium methoxide in 300 ml. of tetrahydrofuran,13.4 ml. of ethyl formate, and a solution of 40.0 g. of1-(4-acetyl-benzenesulfonyl)piperidine in 400 ml. of tetrahydrofuran)and 18.9 g. of cyanoacetamide, there is obtained6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 312°-314° C. after crystallization from methanol-dimethylformamide.

(j) 6-[4-(Diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(diethylaminosulfonyl)benzoylacetaldehyde in 500 ml. of water(prepared from 9.34 g. of sodium methoxide in 300 ml. oftetrahydrofuran, 14.1 ml. of ethyl formate, and a solution of 40.0 g. of4-acetyl-N,N-diethylbenzenesulfonamide in 300 ml. of tetrahydrofuran)and 19.7 g. of cyanoacetamide, there is obtained6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 232°-234° C. after crystallization from aqueous dimethylformamide.

(k)6-[4-[(2-Hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-[(2-hydroxyethyl)aminosulfonyl]benzoylacetaldehyde in 500 ml. of water(prepared from 41.3 g. of sodium methoxide in 400 ml. oftetrahydrofuran, 56.6 g. of ethyl formate, and a solution of 56.5 g. of4-acetyl-N-(2-hydroxyethyl)benzenesulfonamide in 700 ml. oftetrahydrofuran) and 29.7 g. of cyanoacetamide, there is obtained6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 283°-286° C. after crystallization from methanol-dimethylformamide.

(l)6-[4-(3-Hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-(3-hydroxymethyl-1-piperidinylsulfonyl)benzoylacetaldehyde in 1 l. ofwater (prepared from 26.6 g. of sodium methoxide in 250 ml. oftetrahydrofuran, 36.5 g. of ethyl formate, and a solution of 66.5 g. of1-(4-acetyl-benzenesulfonyl)-3-piperidinemethanol in 600 ml. oftetrahydrofuran) and 28.2 g. of cyanoacetamide, there is obtained6-[4-(3-hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 269°-272° C. after crystallization from aqueous dimethylformamide.

(m)6-[4-[(2-Dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinonitrile

From a solution of the sodium salt of4-[(2-dimethylaminoethyl)aminosulfonyl]benzoylacetaldehyde in 1 l. ofwater (prepared from 23.7 g. of sodium methoxide in 240 ml. oftetrahydrofuran, 32.5 g. of ethyl formate, and a solution of 53.9 g. of4-acetyl-N-(2-dimethylaminoethyl)benzenesulfonamide in 540 ml. oftetrahydrofuran) and 25.1 g. of cyanoacetamide, there is obtained6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinonitrile;m.p. 269°-272° C. (dec.) after crystallization fromdimethylformamide/2-propanol.

(n)6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinonitrile

A stirred suspension of 117.7 g. of sodium methoxide in 1 l.tetrahydrofuran and under nitrogen is cooled in ice and treated with 178ml. of ethylformate. The cold mixture is treated dropwise with stirring,with a solution of 190.1 g. of4-acetyl-N,N-bis(2-hydroxyethyl)benzenesulfonamide in 1.75 l.tetrahydrofuran, then stirred at room temperature for 16 hours. Themixture is diluted with 500 ml. of ether and the resulting precipitateof the sodium salt of4-[bis(2-hydroxyethyl)aminosulfonyl]benzoylacetaldehyde is collected byfiltration, washed with ether, and dried. A solution of this sodium saltin 2.5 l. water is adjusted to pH 9 with acetic acid and 98 g. ofN-methylcyanoacetamide is added. The solution is heated to 90° C. for 6hours, then allowed to stand at room temperature for 16 hours. Themixture is acidified to pH 6 with acetic acid and cooled to 0°-5°. Theresulting precipitate of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinonitrileis collected by filtration, washed with water, and dried.Recrystallization from dimethylformamide/water gives the pure product.

(o)6-[(4-dimethylaminosulfonyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinonitrile

From a solution of the sodium salt of4-(dimethylaminosulfonyl)-benzoylacetaldehyde in 2 l. water (preparedfrom 36.1 g. sodium methoxide in 500 ml. tetrahydrofuran, 49.5 g. ofethylformate, and a solution of 137.8 g. of4-acetyl-N,N-dimethylbenzenesulfonamide in 1.4 l. of tetrahydrofuran)and 89.3 g. of N-methylcyanoacetamide, there is obtained6-[(4-dimethylaminosulfonyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinonitrile.Recrystallization from dimethylformamide/water gives the pure product.

E. 6-(Substituted-phenyl)-1,2-dihydro-2-oxonicotinic Acids (a)6-[4-[Bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro2-oxonicotinic Acid

A mixture of 80 g. of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinonitrileand 2.4 l. of 5% aqueous sodium hydroxide is heated at reflux in astainless steel flask for 40 hours. The resulting solution is cooled andacidified with hydrochloric acid. The precipitate of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid is collected by filtration, washed with water and dried; m.p.252°-254° C. after crystallization from aqueousmethanol/dimethylformamide.

In a similar manner, the following acids are prepared by hydrolysis ofthe corresponding nitrile with 5% aqueous sodium hydroxide, followed byacidification of the reaction mixture:

(b) 6-[3-(Aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

M.P. 298-300° C. (dec.) from aqueous dimethylformamide.

(c) 6-[4-(Methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

M.P. 278°-280° C. (dec.) from aqueous dimethylformamide.

(d) 6-[4-(Aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

M.P. 290°-291° C. (dec.) from aqueous dimethylformamide.

(e) 6-[4-(Dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

M.P. 275°-277° C. (dec.) from aqueous dimethylformamide.

(f) 6-[4-(3-Pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

The product is precipitated at pH 4.4 with acetic acid; m.p. 278°-279°C. (dec.) from aqueous dimethylformamide.

(g) 6-[4-(2-Pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

The product is precipitated at pH 4.3 with acetic acid; m.p. 282°-283°C. (dec.) from aqueous ethanolic dimethylformamide.

(h) 6-[4-(Pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

M.P. 292°-294° C. (dec.) from aqueous dimethylformamide.

(i) 6-[4-(1-Piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

M.P. 300°-302° C. (dec.) from ethanolic dimethylformamide.

(j) 6-[4-(Diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic Acid

M.P. 228°-229° C. from 2-propanol/dimethylformamide.

(k)6-[4-[(2-Hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicAcid

M.P. 290°-295° C. (dec.) from aqueous dimethylformamide.

(l)6-[4-(3-Hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinicAcid

M.P. 300°-304° C. from ethanolic dimethylformamide.

(m)6-[4-[(2-Dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicAcid

The product is precipitated at pH 4.5 with dilute hydrochloric acid;m.p. 277°-278° C. (dec.) from ethanolic dimethylformamide.

(n)6-[4-[Bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinicAcid (o)6-[(4-Dimethylaminosulfonyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinicAcid F. 6-(Substituted-phenyl)-1,2-dihydro-2-oxonicotinyl Chlorides (a)6-[3-(Aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl Chloride

A stirred suspension of 2.6 g. of6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 130 ml.of tetrahydrofuran is treated with 1.24 ml. of triethylamine. After afew minutes, the resulting solution is treated with 1.12 ml. oftrimethylsilyl chloride and stirred 1 hour at room temperature. Thesolution is then treated with 1.28 ml. of thionyl chloride and stirredfor 2 hours at room temperature. The resulting solution is diluted with200 ml. of hexane and the precipitate of6-[3-aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride iscollected by filtration, washed with hexane and dried. The acid chlorideis used as such without further purification.

(b) 6-[4-(Methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylChloride

From 5.0 g. of6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 250ml. of tetrahydrofuran, 2.26 ml. of triethylamine, 2.05 ml. oftrimethylsilyl chloride and 2.33 ml. of thionyl chloride, following theprocedure of a) above, there is obtained6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.

(c) 6-[4-(Aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl Chloride

A suspension of 4.0 g. of6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 120 ml.of thionyl chloride is treated with 1 ml. of dimethylformamide andstirred at room temperature for 4 hours. The mixture is diluted with 200ml. of hexane and the precipitate of6-[4-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride iscollected, washed with hexane and dried. The acid chloride is used assuch without further purification.

(d) 6-[4-(Dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylChloride

From 3.5 g. of6-[dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 120ml. of methylene chloride, 1.55 ml. of triethylamine, 1.4 ml. oftrimethylsilyl chloride and 1.6 ml. of thionyl chloride, following theprocedure of a) above, there is obtained6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.

(e) 6-[4-(3-Pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylChloride Hydrochloride

From 4.0 g. of6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in150 ml. of methylene chloride, 1.55 ml. of trimethylamine, 1.4 ml. oftrimethylsilyl chloride and 1.6 ml. of thionyl chloride, following theprocedure of (a) above, there is obtained6-[4-(3-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloridehydrochloride.

(f) 6-[4-(2-Pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylChloride Hydrochloride

From 7.0 g. of6-[4-(2-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in200 ml. of thionyl chloride, and 1.5 ml. of dimethylformamide, followingthe procedure of (c) above, there is obtained6-[4-(2-pyridylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloridehydrochloride.

(g) 6-[4-(1-Pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylChloride

From 4.4 g. of6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in150 ml. of methylene chloride, 1.6 ml. of triethylamine, 1.45 ml. oftrimethylsilyl chloride and 1.7 ml. of thionyl chloride, following theprocedure of a) above, there is obtained6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylchloride.

(h) 6-[4-(1-Piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylChloride

From 5.0 g. of6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in150 ml. of methylene chloride, 2.0 ml. of triethylamine, 1.75 ml. oftrimethylsilyl chloride and 2.0 ml. of thionyl chloride, following theprocedure of a) above, there is obtained6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.

(i) 6-[4-(Diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylChloride

From 6.0 g. of6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in175 ml. of methylene chloride, 2.4 ml. of triethylamine, 2.2 ml. oftrimethylsilyl chloride and 2.5 ml. of thionyl chloride, following theprocedure of a) above, there is obtained6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.

(j)6-[4-[(2-Dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinylChloride Hydrochloride

A suspension of 3.5 g. of6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid in 175 ml. of thionyl chloride is stirred at room temperature for16 hours. The mixture is diluted with 300 ml. of hexane and theprecipitate of6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinylchloride hydrochloride is collected by filtration, washed with hexaneand dried. The acid chloride is used as such without furtherpurification.

(k)6-[(4-dimethylaminosulfonyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinylChloride

Utilizing the procedure of part F, a) but using6-[(4-dimethylaminosulfonyl)phenyl]-1,2-dihydro-1-methyl-2-oxonicotinicacid in place of 6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinicacid, the above named product is obtained.

G. 2,5-Dioxo-1-pyrrolidinyl Esters of 1,2-Dihydro-2-oxonicotinic Acids(a)6-[4-[Bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicAcid, 2,5-Dioxo-1-pyrrolidinyl Ester

A solution of 45 g. of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid and 14.0 g. of N-hydroxysuccinimide in 450 ml. of dimethylformamideis cooled to 0°-5° C. and treated dropwise, with stirring, with asolution of 26.8 g. of N,N'-dicyclohexylcarbodiimide in 30 ml. ofdimethylformamide. The mixture is stirred for 16 hours at roomtemperature, then cooled and filtered to remove by-productN,N'-dicyclohexylurea. The filtrate is diluted with 1.5 l. of 2-propanoland the resulting precipitate of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester is collected by filtration, washedwith cold 2-propanol and dried; m.p. 213°-215.5° C.

(b)6-[4-[(2-Hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicAcid, 2,5-Dioxo-1-pyrrolidinyl Ester

From 3.8 g. of6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid and 1.34 g. of N-hydroxysuccinimide in 60 ml. of dimethylformamide,and 2.56 g. of N,N'-dicyclohexylcarbodiimide in 5 ml. ofdimethylformamide, following the procedure of (a) above, there isobtained6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 203.5°-205° C.

(c)6-[4-(3-Hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinicAcid, 2,5-Dioxo-1-pyrrolidinyl Ester

From 5.0 g. of6-[4-(3-hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinicacid in 130 ml. of dimethylformamide, and 2.89 g. ofN,N'-dicyclohexylcarbodiimide in 10 ml. of dimethylformamide, followingthe procedure of (a) above, there is obtained6-[4-(3-hydroxymethyl-1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 201°-204° C.

(d)6-[4-[Bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl Ester

A solution of 4.43 g. of6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinicacid and 1.34 g. of N-hydroxysuccinimide in 60 ml. dimethylformamide wascooled in ice and treated dropwise with a solution of 2.56 g. ofN,N'-dicyclohexylcarbodiimide in 5 ml. dimethylformamide. The solutionwas allowed to warm to room temperature over 16 hours. The mixture wascooled and the N,N'-dicyclohexylurea filtered off. Addition of 180 ml.of isopropanol to the filtrate precipitated the6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-1-methyl-2-oxonicotinicacid, 2,5-dioxo-1-pyrrolidinyl ester, which was collected by filtration.

H. 6-[4-(Dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinylImidazolide

A stirred suspension of 4.0 g. of6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in32 ml. of N,N-dimethylacetamide is treated with 2.82 g. of1,1-carbonyldiimidazole. The mixture is stirred at 60° C. for 1 hour,cooled and diluted with 100 ml. of ether. The precipitate of6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-oxonicotinyl imidazolideis collected by filtration, washed with ether and dried.

I.D-N-[6-[4-(Dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-2-phenylglycine

A mixture of 16.6 g. of D-(-)-2-phenylglycine, 30 ml. of trimethylsilylchloride and 35 ml. of triethylamine in 1.0 l. of dichloromethane isstirred for 1 hour at room temperature. The resulting solution ofD-N-(trimethylsilyl)-2-phenylglycine, trimethylsilyl ester, is cooled to0°-5° C. and there is added in portions, with stirring, 34 g. of6-[4-dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride,followed by 13.9 ml. of triethylamine. The mixture is stirred at 0°-5°C. for 1 hour, then at room temperature for 2 hours. The mixture ispoured into 1 l. of ice water and the pH adjusted to 8.1 with saturatedaqueous sodium bicarbonate. The aqueous solution is extracted with ethylacetate and the extract discarded. The aqueous solution is thenacidified to pH 2.0 with dilute hydrochloric acid. The resultingprecipitate ofD-N-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-2-phenylglycineis collected by filtration, washed well with water and dried.

We claim:
 1. A compound of the formula ##STR14## andpharmaceutically-acceptable salts thereof; wherein R is hydrogen ormethyl; R₁ is hydrogen, lower alkyl or hydroxy(lower alkyl), R₂ ishydrogen, lower alkyl, hydroxy(lower alkyl), pyridyl or di(loweralkyl)amino(lower alkyl); R₁ R₂ N taken together is 1-pyrrolidinyl,1-piperidinyl or hydroxymethyl-1-piperidinyl, R₃ is phenyl,4-hydroxyphenyl, 2-thienyl or cyclohexa-1,4-dien-1-yl.
 2. The compoundsof claim 1 wherein R₁ and R₂ are hydroxy(lower alkyl).
 3. The compoundsof claim 2 wherein the R₁ R₂ NSO₂ group is in the para position and R₃is p-hydroxyphenyl.
 4. The compound of claim 1 having the nameN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillinand pharmaceutically-acceptable salts thereof.
 5. The compound of claim1 having the nameN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin,sodium salt.
 6. The compound of claim 1 having the nameN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillinand pharmaceutically-acceptable salts thereof.
 7. The compound of claim1 having the nameN-[6-[4-[bis(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillin,sodium salt.
 8. The compound of claim 1 having the nameN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillinand pharmaceutically-acceptable salts thereof.
 9. The compound of claim1 having the nameN-[6-[4-(dimethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillin,sodium salt.
 10. The compound of claim 1 having the nameN-[6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillinand pharmaceutically-acceptable salts thereof.
 11. The compound of claim1 having the nameN-[6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl]amoxicillin,sodium salt.
 12. An antibacterial composition consisting of anantibacterially effective amount of a compound of claim 1 and apharmaceutical carrier.
 13. A method for treating bacterial infectionsin mammals which comprises administering an antibacterially effectiveamount of composition of claim 12.